[unreadable] There is strong biologic plausibility and animal experimental evidence for protection against colorectal cancer by calcium and vitamin D, calcium significantly reduced adenoma recurrence in a large clinical trial in humans, and the observational literature strongly supports protection from vitamin D. A close physiological relationship between calcium and vitamin D has long been known. Yet, the effects of calcium and vitamin D, individually or jointly, on the normal human colorectal epithelium remain unknown. There have been no clinical trials involving vitamin D individually or jointly with calcium related to colorectal cancer chemoprevention in humans. There are currently no generally accepted pre-neoplastic biomarkers of risk for colorectal cancer. Based on recent advances in understanding the molecular basis of colorectal cancer, we developed a panel of newer, plausible, reliable, immunohistochemically detected biomarkers that provides molecular phenotyping of the normal appearing colorectal epithelium: 1) inflammation (COX-2), 2) the expression of genes involved in the normal structure and function of the colorectal epithelium that have been found to be altered early in the two major colorectal carcinogenesis pathways (ARC, beta-catenin, E-cadherin, MLH1), 3) cell cycle events in colorectal epithelial crypt cells (long-term proliferation: telomerase; apoptosis inhibition and promotion: bcl-2, bax), and 4) autocrine/paracrine growth promotion and inhibition factors (TGFalpha, TGFbeta1,) that has not yet been tested in a chemoprevention trial. To address these needs, we will add measuring this biomarker panel to an ongoing multi- center, randomized, double-blind, placebo-controlled, 2x2 factorial clinical trial (n = 1,964) testing the efficacy of calcium 1,200 mg/day and/or vitamin D31,000 ILJ/day vs placebo in reducing recurrent sporadic colorectal adenomas over 3-5 years, in order to determine whether calcium and/or vitamin D can favorably modulate the panel of biomarkers and whether this modulation predicts adenoma recurrence. For the biomarker measurements, biopsies of normal- appearing rectal mucosa will be obtained from 1,328 (68%) of participants at 3- or 5-year follow-up colonoscopy. In addition, on a subset (n = 200) of these participants (50/treatment group), biopsies of normal-appearing rectal mucosa will be taken 'non-prep' at randomization, one year following randomization, and two weeks prior to 3 - 5 year follow-up colonoscopy; biopsies of normal appearing mucosa will also be taken from three colon sites (rectum, mid- sigmoid colon, and proximal ascending colon) during follow-up colonoscopies. We assert that using biological measurements of risk, as they have for ischemic heart disease, will result in a decline in colorectal cancer incidence and mortality. The proposed project is borne of this vision, and has intertwined missions of investigating the efficacy of two plausible and evidentially well-supported dietary agents, calcium and vitamin D, in modulating a plausible panel of molecular phenotypic biomarkers of risk for colorectal neoplasia, and determining whether this modulation predicts reduced recurrence of colorectal neoplasms. [unreadable] [unreadable]